Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer

Ping-Bao Zhang; Zi-Li Huang; Yong-Hua Xu; Jin Huang; Xin-Yu Huang; Xiu-Yan Huang

doi:10.1186/s12935-019-1056-y

Systematic analysis of gene expression profiles reveals prognostic stratification and underlying mechanisms for muscle-invasive bladder cancer

Cancer Cell Int. 2019 Dec 16:19:337. doi: 10.1186/s12935-019-1056-y. eCollection 2019.

Authors

Ping-Bao Zhang^{1

2}, Zi-Li Huang³, Yong-Hua Xu³, Jin Huang⁴, Xin-Yu Huang¹, Xiu-Yan Huang¹

Affiliations

¹ 1Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233 People's Republic of China.
² 2Department of Urinary Surgery, Affiliated Hospital of Nantong University, Nantong, 226021 People's Republic of China.
³ 3Department of Radiology, Xuhui Central Hospital of Zhongshan Hospital, Fudan University, Shanghai, 200031 People's Republic of China.
⁴ 4Department of Pathology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233 People's Republic of China.

Abstract

Background: Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice.

Methods: This study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways.

Results: In the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC.

Conclusions: In summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.

Keywords: Drug-target; M2 macrophage; Muscle-invasive bladder cancer (MIBC); Overall survival; Stratification.